Thursday, October 27, 2011

Hot off the presses! Oct 28 Immunity

The Oct 28 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • The End and After: How Dying Cells Impact the Living Organism
    - Immunity 35(4):441-444 (2011)
    All cells die, but the manner of death dictates interactions with living cells and consequences for the organism, especially with respect to the immune response. Here we discuss the different modes of cell death as they relate to this rapidly evolving field.
  • Beginnings of a Good Apoptotic Meal: The Find-Me and Eat-Me Signaling Pathways
    - Immunity 35(4):445-455 (2011)
    Prompt and efficient clearance of apoptotic cells is necessary to prevent secondary necrosis of dying cells and to avoid immune responses to autoantigens. Recent studies have shed light on how apoptotic cells through soluble "find-me" signals advertise their presence to phagocytes at the earliest stages of cell death. Phagocytes sense the find-me signal gradient, and in turn the presence of dying cells, and migrate to their vicinity. The apoptotic cells also expose specific "eat-me" signals on their surface that are recognized by phagocytes through specific engulfment receptors. This review covers the recent progress in the areas of find-me and eat-me signals and how these relate to prompt and immunologically silent clearance of apoptotic cells.
  • Cell Death in the Maintenance and Abrogation of Tolerance: The Five Ws of Dying Cells
    - Immunity 35(4):456-466 (2011)
    The mammalian immune system continually faces death in the form of its own dead and dying cells that arise during normal tissue turnover, infections, cellular damage, and cancer. Complex decisions must then be made that will permit a protective response to pathogens, while at the same time destroying tumors but not attacking vital systems of the host that could lead to autoimmunity. By using an investigative technique termed the five Ws (who, what, when, where, and why), we will examine how the immune system responds to antigens generated via cell death. This analysis will give us a better understanding of the molecular differences fundamental to tolerogenic or immunogenic cell death, the cells that sense and react to the dead cells, and the consequences of these fundamental elements on the maintenance or abrogation of tolerance.
  • Tumor Promotion via Injury- and Death-Induced Inflammation
    - Immunity 35(4):467-477 (2011)
    Inhibition of programmed cell death is considered to be a major aspect of tumorigenesis. Indeed, several key oncogenic transcription factors, such as NF-κB and STAT3, exert their tumor-promoting activity at least in part through upregulation of survival genes. However, many cancers develop in response to chronic tissue injury, in which the resulting cell death increases the tumorigenic potential of the neighboring cells. In this review, we discuss a resolution to this paradox based on cell death-mediated induction of tumor promoting inflammatory cytokines, which enhance cell survival and trigger compensatory proliferation in response to tissue injury.
  • Dying to Replicate: The Orchestration of the Viral Life Cycle, Cell Death Pathways, and Immunity
    - Immunity 35(4):478-490 (2011)
    Manipulation of cell death pathways has been identified as a common feature of host-microbe interactions. We examine two examples: influenza A as a representative acute infection and cytomegalovirus as an example of chronic infection. From the perspective of viral entry, replication, and transmission, we identify points of interconnection with the host response to infection, namely the induction of host cell death, inflammation, and immunity. Following from this analysis, we argue that the evolution and fine-tuned regulation of death-associated genes may result from constant microbial pressure—past and present—that helped to support and coordinate cell death programs within the host. Interestingly, the delay in host cell death allows time for the virus to replicate while perturbations in cell death allow the host cell to initiate an immune response. This may represent a genetically encoded trade-off ensuring survival of both host and virus, or it may be a part of t! he complex agenda of infectious microbes.
  • Dynamiting Viruses with MxA
    - Immunity 35(4):491-493 (2011)
    The crystal structure of the interferon-induced member of the dynamin family MxA presented by in this issue of Immunity reveals the molecule's higher-order structure, thereby providing insight into the protein's antiviral action as a molecular machine.
  • Dual Face Apoptotic Machinery: From Initiator of Apoptosis to Guardian of Necroptosis
    - Immunity 35(4):493-495 (2011)
    In this issue of Immunity, show that skin-specific ablation of the adaptor protein FADD sensitizes keratinocytes to RIPK3-dependent necrotic cell death, which leads to severe skin inflammation.
  • Memory: The Incomplete Unhappening of Differentiation
    - Immunity 35(4):496-498 (2011)
    The signals that regulate the differentiation of central and effector memory T cells remain unclear. In this issue of Immunity, and implicate the differential expression of transcription factors in driving memory subtypes.
  • Orphan Cytokine Reveals IL-17 Family Secret
    - Immunity 35(4):498-500 (2011)
    The biology of interleukin-17C (IL-17C) has remained largely a mystery for more than a decade. , in this issue of Immunity, and two other reports () demonstrate that IL-17C has broad functions in a variety of tissues.
  • The DNA-Binding Protein CTCF Limits Proximal Vκ Recombination and Restricts κ Enhancer Interactions to the Immunoglobulin κ Light Chain Locus
    - Immunity 35(4):501-513 (2011)
    Regulation of immunoglobulin (Ig) V(D)J gene rearrangement is dependent on higher-order chromatin organization. Here, we studied the in vivo function of the DNA-binding zinc-finger protein CTCF, which regulates interactions between enhancers and promoters. By conditional deletion of the Ctcf gene in the B cell lineage, we demonstrate that loss of CTCF allowed Ig heavy chain recombination, but pre-B cell proliferation and differentiation was severely impaired. In the absence of CTCF, the Igκ light chain locus showed increased proximal and reduced distal Vκ usage. This was associated with enhanced proximal Vκ and reduced Jκ germline transcription. Chromosome conformation capture experiments demonstrated that CTCF limits interactions of the Igκ enhancers with the proximal Vκ gene region and prevents inappropriate interactions between these strong enhancers and elements outside the Igκ locus. Thus, although Ig gene recombination can occur in the absenc! e of CTCF, it is a critical factor determining Vκ segment choice for recombination.
  • Structure of Myxovirus Resistance Protein A Reveals Intra- and Intermolecular Domain Interactions Required for the Antiviral Function
    - Immunity 35(4):514-525 (2011)
    Human myxovirus resistance protein 1 (MxA) is an interferon-induced dynamin-like GTPase that acts as a cell-autonomous host restriction factor against many viral pathogens including influenza viruses. To study the molecular principles of its antiviral activity, we determined the crystal structure of nucleotide-free MxA, which showed an extended three-domain architecture. The central bundle signaling element (BSE) connected the amino-terminal GTPase domain with the stalk via two hinge regions. MxA oligomerized in the crystal via the stalk and the BSE, which in turn interacted with the stalk of the neighboring monomer. We demonstrated that the intra- and intermolecular domain interplay between the BSE and stalk was essential for oligomerization and the antiviral function of MxA. Based on these results, we propose a structural model for the mechano-chemical coupling in ring-like MxA oligomers as the principle mechanism for this unique antiviral effector protein.
  • Evolutionarily Conserved Features Contribute to αβ T Cell Receptor Specificity
    - Immunity 35(4):526-535 (2011)
    αβ T cell receptors (TCRs) bind specifically to foreign antigens presented by major histocompatibility complex proteins (MHC) or MHC-like molecules. Accumulating evidence indicates that the germline-encoded TCR segments have features that promote binding to MHC and MHC-like molecules, suggesting coevolution between TCR and MHC molecules. Here, we assess directly the evolutionary conservation of αβ TCR specificity for MHC. Sequence comparisons showed that some Vβs from distantly related jawed vertebrates share amino acids in their complementarity determining region 2 (CDR2). Chimeric TCRs containing amphibian, bony fish, or cartilaginous fish Vβs can recognize antigens presented by mouse MHC class II and CD1d (an MHC-like protein), and this recognition is dependent upon the shared CDR2 amino acids. These results indicate that features of the TCR that control specificity for MHC and MHC-like molecules were selected early in evolution and maintained betw! een species that last shared a common ancestor more than 400 million years ago.
  • Pathogen-Derived Effectors Trigger Protective Immunity via Activation of the Rac2 Enzyme and the IMD or Rip Kinase Signaling Pathway
    - Immunity 35(4):536-549 (2011)
    Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.
  • Mast Cells Condition Dendritic Cells to Mediate Allograft Tolerance
    - Immunity 35(4):550-561 (2011)
    Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior ("conditioning") to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on t! he migration and function of tolerogenic DCs.
  • Mast Cell Interleukin-2 Production Contributes to Suppression of Chronic Allergic Dermatitis
    - Immunity 35(4):562-571 (2011)
    The incidence of chronic allergic dermatitis is rapidly increasing. Regulatory control of this disease has not been adequately explored. Here we report that mast cell-derived interleukin-2 (IL-2) contributes to the suppression of chronic allergic dermatitis. Mice deficient in IL-2 production, or deficient in mast cells (KitW-sh/W-sh), showed exacerbated dermatitis upon repeated oxazolone challenge when compared to their wild-type counterparts. Adoptive transfer of wild-type, but not Il2-/-, mast cells into KitW-sh/W-sh mice dampened the inflammatory response. During the course of disease, mast cell expansion occurred at the site of inflammation and also in the spleen, where production of IL-2 by mast cells was markedly enhanced. In the absence of mast cell IL-2 production, the ratio of activated to regulatory T cells at the site of inflammation was increased. Thus, MC-derived IL-2 contributes to the maintenance of suppression in chronic allergic skin inflammation.
  • The Adaptor Protein FADD Protects Epidermal Keratinocytes from Necroptosis In Vivo and Prevents Skin Inflammation
    - Immunity 35(4):572-582 (2011)
    Epidermal keratinocytes provide an essential structural and immunological barrier forming the first line of defense against potentially pathogenic microorganisms. Mechanisms regulating barrier integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases. Here, we show that epidermal keratinocyte-restricted deficiency of the adaptor protein FADD (FADDE-KO) induced severe inflammatory skin lesions in mice. The development of skin inflammation in FADDE-KO mice was triggered by RIP kinase 3 (RIP3)-mediated programmed necrosis (termed necroptosis) of FADD-deficient keratinocytes, which was partly dependent on the deubiquitinating enzyme CYLD and tumor necrosis factor (TNF)-TNF receptor 1 signaling. Collectively, our findings provide an in vivo experimental paradigm that regulation of necroptosis in keratinocytes is important for the maintenance of immune homeostasis and! the prevention of chronic inflammation in the skin.
  • Opposing Signals from the Bcl6 Transcription Factor and the Interleukin-2 Receptor Generate T Helper 1 Central and Effector Memory Cells
    - Immunity 35(4):583-595 (2011)
    Listeria monocytogenes infection generates T helper 1 (Th1) effector memory cells and CC chemokine receptor 7 (CCR7)+ cells resembling central memory cells. We tracked endogenous L. monocytogenes-specific CD4+ T cells to determine how these memory cells are formed. Two effector cell populations were already present several days after infection. One highly expressed the T-bet transcription factor and produced Th1 memory cells in an interleukin-2 (IL-2) receptor-dependent fashion. The other resided in the T cell areas, expressed CCR7 and CXC chemokine receptor 5 (CXCR5), and like follicular helper cells depended on the Bcl6 transcription factor and inducible costimulator ligand on B cells. The CCR7+CXCR5+ effector cells produced similar memory cells that generated diverse effector cell populations in a secondary response. Thus, Th1 effector memory and follicular helper-like central memory cells are produced from early effector cell populations that diverge in response to! signals from the IL-2 receptor, Bcl6, and B cells.
  • Pivotal Role of Dermal IL-17-Producing γδ T Cells in Skin Inflammation
    - Immunity 35(4):596-610 (2011)
    Interleukin-23 (IL-23) and CD4+ T helper 17 (Th17) cells are thought to be critical in psoriasis pathogenesis. Here, we report that IL-23 predominantly stimulated dermal γδ T cells to produce IL-17 that led to disease progression. Dermal γδ T cells constitutively expressed the IL-23 receptor (IL-23R) and transcriptional factor RORγt. IL-17 production from dermal γδ T cells was independent of αβ T cells. The epidermal hyperplasia and inflammation induced by IL-23 were significantly decreased in T cell receptor δ-deficient (Tcrd−/−) and IL-17 receptor-deficient (Il17ra−/−) mice but occurred normally in Tcra−/− mice. Imiquimod-induced skin pathology was also significantly decreased in Tcrd−/− mice. Perhaps further promoting disease progression, IL-23 stimulated dermal γδ T cell expansion. In psoriasis patients, γδ T cells were greatly increased in affected skin and produced large amounts of IL-17. Thus, IL-23-respo! nsive dermal γδ T cells are the major IL-17 producers in the skin and may represent a novel target for the treatment of psoriasis.
  • Interleukin-17C Promotes Th17 Cell Responses and Autoimmune Disease via Interleukin-17 Receptor E
    - Immunity 35(4):611-621 (2011)
    Although several interleukin-17 (IL-17) family members and their receptors have been recently appreciated as important regulators in inflammatory diseases, the function of other IL-17 cytokines and IL-17 receptor-like molecules is unclear. Here we show that an IL-17 cytokine family member, IL-17C, was induced in a Th17 cell-dependent autoimmune disease and was required for its pathogenesis. IL-17C bound to IL-17RE, a member of IL-17 receptor family whose full-length isoform was selectively expressed in Th17 cells and signaled via an IL-17RA-RE receptor complex and the downstream adaptor Act1. IL-17C-IL-17RE induced the expression of a nuclear IkappaB family member, IκBζ, in Th17 cells to potentiate the Th17 cell response. Thus, our work has identified a cytokine-receptor pair with important function in regulating proinflammatory responses. This pathway may be targeted to treat autoimmune diseases.
  • Functional and Epigenetic Studies Reveal Multistep Differentiation and Plasticity of In Vitro-Generated and In Vivo-Derived Follicular T Helper Cells
    - Immunity 35(4):622-632 (2011)
    Follicular T helper (Tfh) cells provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated protein (SAP) prevent GC formation because of defective T cell-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent "Tfh-like" cells that expressed interleukin-21, Tfh cell markers, and Bcl6 and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wild-type, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2, and Th17 cells could be reprogrammed to obtain Tfh cell characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3, and Rorc in Tfh-like and ex vivo Tfh cells and on Bcl6 in no! n-Tfh cells, supporting the concept of plasticity between Tfh and other Th cell populations.
  • Differential Expression of Ly6C and T-bet Distinguish Effector and Memory Th1 CD4+ Cell Properties during Viral Infection
    - Immunity 35(4):633-646 (2011)
    CD4+ T cells differentiate into multiple effector types, but it is unclear how they form memory T cells during infection in vivo. Profiling virus-specific CD4+ T cells revealed that effector cells with T helper 1 (Th1) or T follicular helper (Tfh) cell characteristics differentiated into memory cells, although expression of Tfh cell markers declined over time. In contrast to virus-specific effector CD8+ T cells, increased IL-7R expression was not a reliable marker of CD4+ memory precursor cells. However, decreased Ly6C and T-bet (Tbx21) expression distinguished a subset of Th1 cells that displayed greater longevity and proliferative responses to secondary infection. Moreover, the gene expression profile of Ly6CloT-betint Th1 effector cells was virtually identical to mature memory CD4+ T cells, indicating early maturation of memory CD4+ T cell features in this subset during acute viral infection. This study provides a framework for memory CD4+ T cell development after a! cute viral infection.
  • Mapping a Dynamic Innate Immunity Protein Interaction Network Regulating Type I Interferon Production
    - Immunity 35(4):647-648 (2011)
  • Pivotal Role of Dermal IL-17-Producing γδ T Cells in Skin Inflammation
    - Immunity 35(4):649 (2011)

No comments: